Details of Disease

Disease Name

Cytochrome-c oxidase deficiency disease

deficiency of mitochondrial respiratory chain complex4; isolated cytochrome C oxidase deficiency; Cox deficiency; Complex 4 mitochondrial respiratory chain deficiency; Complex IV deficiency; mitochondrial Complex 4 deficiency; cytochrome C oxidase deficiency; COX deficiency; cytochrome-C oxidase deficiency; mitochondrial complex IV deficiency; isolated COX deficiency; Cytochrome C Oxidase Deficiency; cytochrome-c oxidase deficiency disease; isolated mitochondrial respiratory chain complex IV deficiency

Definition

A very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome-C oxidase. It may be manifested as an isolated myopathy or a systemic disorder. Signs and symptoms include myotonia, dysfunction of the heart, kidney, and brain, and lactic acidosis.|Reason: duplicate. This will be merged with MONDO:0033885 mitochondrial complex IV deficiency, nuclear-type

Disease Hierarchy

DISCJSA1: Mitochondrial complex deficiency

DISK7N3G: Cytochrome-c oxidase deficiency disease

Disease Identifiers

MONDO ID

MONDO_0009068

MESH ID

D030401

UMLS CUI

C0268237

MedGen ID

75662

SNOMED CT ID

67434000

General Information of Disease (ID: DISK7N3G)

Molecular Interaction Atlas (MIA) of This Disease

Molecular Interaction Atlas (MIA)

This Disease Is Related to 2 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
COX17	TT0F26C	Strong	Biomarker	[1]
GAA	TTLPC70	Strong	Altered Expression	[2]
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This Disease Is Related to 2 DME Molecule(s)

Gene Name	DME ID	Evidence Level	Mode of Inheritance	REF
CHKB	DEHWR6V	Strong	Genetic Variation	[3]
FARS2	DE0WGR8	Strong	Genetic Variation	[4]
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This Disease Is Related to 45 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
CCS	OTXHT3QO	Limited	Genetic Variation	[5]
COA5	OTK12EG7	Limited	Autosomal recessive	[6]
COX3	OTNNGBYJ	Limited	GermlineCausalMutation	[7]
COA3	OT4BMIYV	Supportive	Autosomal recessive	[8]
COX10	OTCYIS0L	Supportive	Autosomal recessive	[9]
COX14	OTQ378WN	Supportive	Autosomal recessive	[10]
COX20	OTXL7EP2	Supportive	Autosomal recessive	[11]
COX4I1	OTU0FC24	Supportive	Autosomal recessive	[12]
COX5A	OTP0961M	Supportive	Autosomal recessive	[13]
COX6A2	OTQR5SXD	Supportive	Autosomal recessive	[14]
COX8A	OTU0NR39	Supportive	Autosomal recessive	[15]
MT-CO1	OTG3O9BN	Supportive	Autosomal recessive	[16]
PET117	OT76T8O0	Supportive	Autosomal recessive	[17]
CEP89	OT1VEFSL	Strong	Genetic Variation	[18]
COA6	OTT52V2I	Strong	Genetic Variation	[19]
COA7	OTRQJYL6	Strong	Genetic Variation	[20]
COX15	OTUIYHIW	Strong	Genetic Variation	[21]
COX16	OTEYPTJP	Strong	Genetic Variation	[22]
COX18	OTIRSG4N	Strong	Genetic Variation	[23]
COX2	OTTMVBJJ	Strong	Biomarker	[24]
COX4I2	OTB98B21	Strong	Biomarker	[25]
COX6A1	OT77MV8G	Strong	Biomarker	[26]
COX7A1	OTHV25GG	Strong	Biomarker	[26]
CPOX	OTIAY121	Strong	Biomarker	[27]
EHHADH	OTBAAHL5	Strong	Genetic Variation	[2]
ETHE1	OTP9A2BQ	Strong	Biomarker	[25]
FASTKD2	OTD635WX	Strong	Biomarker	[28]
GBE1	OTK2N05B	Strong	Biomarker	[2]
GFM2	OT51TIMY	Strong	Biomarker	[29]
HADHA	OTO557N2	Strong	Genetic Variation	[30]
MRPL44	OT27ZC26	Strong	Altered Expression	[31]
MRRF	OT6AHPVG	Strong	Biomarker	[29]
NDUFA4	OTDVH3QG	Strong	Biomarker	[32]
OTOA	OTBTEFIE	Strong	Genetic Variation	[30]
PET100	OTQ0J3DT	Strong	Autosomal recessive	[6]
PLCE1	OTJISZOX	Strong	Genetic Variation	[33]
SCO2	OTJQQDRS	Strong	Genetic Variation	[30]
SIRT4	OT5S0J23	Strong	Biomarker	[34]
STXBP1	OTRYA8C3	Strong	Genetic Variation	[35]
SURF1	OTAINRSS	Strong	Genetic Variation	[36]
TACO1	OTK1WUBL	Strong	Autosomal recessive	[6]
COA8	OTOM9C4A	Definitive	Autosomal recessive	[37]
COX6B1	OTNKXYQI	Definitive	Autosomal recessive	[6]
LRPPRC	OTXSK5LP	Definitive	Autosomal recessive	[38]
SCO1	OTC45UGB	Definitive	Autosomal recessive	[6]
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⏷ Show the Full List of 45 DOT(s)

References

1	Characterization of human SCO1 and COX17 genes in mitochondrial cytochrome-c-oxidase deficiency.Biochem Biophys Res Commun. 2000 Sep 24;276(2):530-3. doi: 10.1006/bbrc.2000.3495.
2	Neonatal metabolic myopathies.Semin Perinatol. 1999 Apr;23(2):125-51. doi: 10.1016/s0146-0005(99)80046-9.
3	Congenital megaconial myopathy due to a novel defect in the choline kinase Beta gene.Arch Neurol. 2012 May;69(5):657-61. doi: 10.1001/archneurol.2011.2333.
4	Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency.Biochim Biophys Acta. 2014 Jan;1842(1):56-64. doi: 10.1016/j.bbadis.2013.10.008. Epub 2013 Oct 24.
5	Isolated cytochrome c oxidase deficiency in G93A SOD1 mice overexpressing CCS protein.J Biol Chem. 2008 May 2;283(18):12267-75. doi: 10.1074/jbc.M708523200. Epub 2008 Mar 11.
6	Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
7	Childhood onset mitochondrial myopathy and lactic acidosis caused by a stop mutation in the mitochondrial cytochrome c oxidase III gene.J Med Genet. 2002 Nov;39(11):812-6. doi: 10.1136/jmg.39.11.812.
8	Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature. J Med Genet. 2015 Mar;52(3):203-7. doi: 10.1136/jmedgenet-2014-102914. Epub 2015 Jan 20.
9	A mutation in the human heme A:farnesyltransferase gene (COX10 ) causes cytochrome c oxidase deficiency. Hum Mol Genet. 2000 May 1;9(8):1245-9. doi: 10.1093/hmg/9.8.1245.
10	Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis. Am J Hum Genet. 2012 Jan 13;90(1):142-51. doi: 10.1016/j.ajhg.2011.11.027.
11	A mutation in the FAM36A gene, the human ortholog of COX20, impairs cytochrome c oxidase assembly and is associated with ataxia and muscle hypotonia. Hum Mol Genet. 2013 Feb 15;22(4):656-67. doi: 10.1093/hmg/dds473. Epub 2012 Nov 2.
12	Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression, intellectual disability, and seizures. Am J Med Genet A. 2019 Oct;179(10):2138-2143. doi: 10.1002/ajmg.a.61288. Epub 2019 Jul 10.
13	Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and failure to thrive. Hum Mutat. 2017 Jun;38(6):692-703. doi: 10.1002/humu.23210. Epub 2017 Mar 23.
14	COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency. Ann Neurol. 2019 Aug;86(2):193-202. doi: 10.1002/ana.25517. Epub 2019 Jul 2.
15	Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy. Brain. 2016 Feb;139(Pt 2):338-45. doi: 10.1093/brain/awv357. Epub 2015 Dec 17.
16	Metabolic consequences of a novel missense mutation of the mtDNA CO I gene. Hum Mol Genet. 2002 Aug 1;11(16):1797-805. doi: 10.1093/hmg/11.16.1797.
17	Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions. Hum Genet. 2017 Jun;136(6):759-769. doi: 10.1007/s00439-017-1794-7. Epub 2017 Apr 6.
18	CEP89 is required for mitochondrial metabolism and neuronal function in man and fly.Hum Mol Genet. 2013 Aug 1;22(15):3138-51. doi: 10.1093/hmg/ddt170. Epub 2013 Apr 10.
19	Mutations in COA6 cause cytochrome c oxidase deficiency and neonatal hypertrophic cardiomyopathy.Hum Mutat. 2015 Jan;36(1):34-8. doi: 10.1002/humu.22715. Epub 2014 Nov 18.
20	Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.EMBO Mol Med. 2019 May;11(5):e9561. doi: 10.15252/emmm.201809561.
21	Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency. J Med Genet. 2005 May;42(5):e28. doi: 10.1136/jmg.2004.029926.
22	Studies of COX16, COX19, and PET191 in human cytochrome-c oxidase deficiency.Arch Neurol. 2004 Dec;61(12):1935-7. doi: 10.1001/archneur.61.12.1935.
23	Mutation analysis of COX18 in 29 patients with isolated cytochrome c oxidase deficiency.J Hum Genet. 2009 Jul;54(7):419-21. doi: 10.1038/jhg.2009.36. Epub 2009 Apr 17.
24	Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies.Cell Metab. 2015 Jun 2;21(6):823-33. doi: 10.1016/j.cmet.2015.04.012. Epub 2015 May 7.
25	Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy.Antioxid Redox Signal. 2011 Jul 15;15(2):353-62. doi: 10.1089/ars.2010.3520. Epub 2011 Feb 25.
26	Assembly of nuclear DNA-encoded subunits into mitochondrial complex IV, and their preferential integration into supercomplex forms in patient mitochondria.FEBS J. 2009 Nov;276(22):6701-13. doi: 10.1111/j.1742-4658.2009.07384.x. Epub 2009 Oct 16.
27	LRPPRC mutations cause a phenotypically distinct form of Leigh syndrome with cytochrome c oxidase deficiency. J Med Genet. 2011 Mar;48(3):183-9. doi: 10.1136/jmg.2010.081976. Epub 2011 Jan 25.
28	Identification of FASTKD2 compound heterozygous mutations as the underlying cause of autosomal recessive MELAS-like syndrome.Mitochondrion. 2017 Jul;35:54-58. doi: 10.1016/j.mito.2017.05.005. Epub 2017 May 9.
29	Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene.Neuromuscul Disord. 2008 Jun;18(6):453-9. doi: 10.1016/j.nmd.2008.04.006. Epub 2008 May 27.
30	Exome-based search for recurrent disease-causing alleles in Russian population.Eur J Med Genet. 2019 Jul;62(7):103656. doi: 10.1016/j.ejmg.2019.04.013. Epub 2019 Apr 24.
31	Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy. J Med Genet. 2013 Mar;50(3):151-9. doi: 10.1136/jmedgenet-2012-101375. Epub 2013 Jan 12.
32	NDUFA4 (Renamed COXFA4) Is a Cytochrome-c Oxidase Subunit.Trends Endocrinol Metab. 2018 Jul;29(7):452-454. doi: 10.1016/j.tem.2018.03.009. Epub 2018 Apr 7.
33	Respiratory-chain deficiency presenting as diffuse mesangial sclerosis with NPHS3 mutation.Pediatr Nephrol. 2011 Jul;26(7):1157-61. doi: 10.1007/s00467-011-1814-0. Epub 2011 Mar 2.
34	Alterations of sirtuins in mitochondrial cytochrome c-oxidase deficiency.PLoS One. 2017 Oct 23;12(10):e0186517. doi: 10.1371/journal.pone.0186517. eCollection 2017.
35	A novel mutation in STXBP1 causing epileptic encephalopathy (late onset infantile spasms) with partial respiratory chain complex IV deficiency.Eur J Med Genet. 2013 Dec;56(12):683-5. doi: 10.1016/j.ejmg.2013.09.013. Epub 2013 Oct 3.
36	Tissue- and species-specific differences in cytochrome c oxidase assembly induced by SURF1 defects.Biochim Biophys Acta. 2016 Apr;1862(4):705-715. doi: 10.1016/j.bbadis.2016.01.007. Epub 2016 Jan 13.
37	Mutations in CEP78 Cause Cone-Rod Dystrophy and Hearing Loss Associated with Primary-Cilia Defects. Am J Hum Genet. 2016 Sep 1;99(3):770-776. doi: 10.1016/j.ajhg.2016.07.009.
38	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.